Psychopathology can be viewed as a hierarchy of correlated dimensions. Many studies have supported this conceptualization, but they have used alternative statistical models with differing ...interpretations. In bifactor models, every symptom loads on both the general factor and 1 specific factor (e.g., internalizing), which partitions the total explained variance in each symptom between these orthogonal factors. In second-order models, symptoms load on one of several correlated lower-order factors. These lower-order factors load on a second-order general factor, which is defined by the variance shared by the lower-order factors. Thus, the factors in second-order models are not orthogonal. Choosing between these valid statistical models depends on the hypothesis being tested. Because bifactor models define orthogonal phenotypes with distinct sources of variance, they are optimal for studies of shared and unique associations of the dimensions of psychopathology with external variables putatively relevant to etiology and mechanisms. Concerns have been raised, however, about the reliability of the orthogonal specific factors in bifactor models. We evaluated this concern using parent symptom ratings of 9-10 year olds in the ABCD Study. Psychometric indices indicated that all factors in both bifactor and second-order models exhibited at least adequate construct reliability and estimated replicability. The factors defined in bifactor and second-order models were highly to moderately correlated across models, but have different interpretations. All factors in both models demonstrated significant associations with external criterion variables of theoretical and clinical importance, but the interpretation of such associations in second-order models was ambiguous due to shared variance among factors.
General Scientific Summary
Some investigators have proposed that viewing the correlated symptoms of psychopathology as a hierarchy in which all symptoms are related to both a general (p) factor of psychopathology and a more specific factor will make it easier to distinguish potential risk factors and mechanisms that are nonspecifically related to all forms of psychopathology versus those that are associated with specific dimensions of psychopathology. Parent ratings of child psychopathology items from the Adolescent Brain Cognitive Development (ABCD) Study were analyzed using two alternative statistical models of the proposed hierarchy. All factors of psychopathology defined in both bifactor and second-order models demonstrated adequate psychometric properties and criterion validity, but associations of psychopathology factors with external variables were more easily interpreted in bifactor than in second-order models.
To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM).
A total of 125 patients with newly ...diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m(2) daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively.
Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study.
The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.
Hairy cell leukemia (HCL) comprises the clonal malignancies classical and variant hairy cell leukemia (vHCL). Classical HCL (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutations ...while ~50% of vHCL have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 - wild type vHCL are not well defined. Therefore, we performed deep targeted mutational and copy number (CN) analysis of cHCL (n=53) and vHCL (n=8) to gain additional insights into the pathogenesis and mechanisms of therapeutic resistance in HCL.
Diagnostic bone marrow (BM) or peripheral blood (PB) mononuclear cells (MNCs) were obtained from 53 cHCL and 8 vHCL patients from multiple centers. Mutational and CN analysis of MNCs (and FACS-purified HCL cells for some cases) was performed using a targeted next-generation sequencing assay, which sequences all coding regions of 585 genes recurrently mutated in leukemias, lymphomas, and solid tumors.
Of the 53 cHCL patients, 100% were marked by BRAFV600E mutations, and the next most commonly mutated genes were the histone methyltransferase KMT2C (MLL3) and CDKN1B occurring in 15% (8/53) and 11% (6/53) of patients, respectively. Other recurrent mutations in cHCL affected genes involved in transcriptional regulation (BRD4, CEBPA, CREBBP, RUNX1, EP300, and MED12), Notch signaling (NOTCH1 and NOTCH2), and DNA repair (RAD50) (Fig. A). The most recurrent copy alterations in cHCL were deletions of chromosome 7q and 13q and gains of chromosome 5. Chromosome 7q and 13q deletions were confirmed by FISH. While recurrent 7q deletions have previously been reported in cHCL, genes in the minimally deleted region of 7q were not known and identified here to include SMO (7q32) and BRAF (7q34). Recurrent 13q deletions in cHCL include the tumor suppressor RB1 and the miR-15a and miR-16-1 microRNA cluster at 13q14.3 (Fig. B-D).
Sequencing across 8 additional vHCL patients identified change-of-function mutations in both CCND3 and U2AF1, each in 13% (1/8) of vHCL patients and hotspot mutations in TP53 (38%; 3/8) (Fig. E). The CCND3 and U2AF1 mutations were absent in cHCL suggesting additional genetic differences between cHCL and vHCL. These findings may have therapeutic relevance as CCND3 mutations are thought to confer sensitivity to CDK4/CDK6 inhibitors while those in U2AF1 confer sensitivity to spliceosome inhibitors. Other mutations affecting genes involved in transcriptional regulation (CEBPA, CREBBP, DDX3X, and PBRM1) and chromatin remodeling (KMT2C, KDM6A, and KDM5C) were also identified (Fig. E). As with cHCL, chromosome 7q deletions were also present in vHCL and always included BRAF (7q34). Additionally, we identified recurrent 3p deletions in vHCL, which include a critical tumor suppressor locus encoding VHL, SETD2, BAP1, and PBRM1 (Fig. F).
Prior studies have identified acquired KRAS mutations as driving vemurafenib resistance in HCL. Here we identified an activating mutation in NRAS in a treatment naïve cHCL patient. In addition, genomic analysis of the pre-treatment sample from a patient that developed de novo vemurafenib resistance uncovered a clonal hemizygous BRAFV600E mutation, as well as heterozygous deletions of BRAF, NF1, NF2, and TP53 (Fig. G). Consistent with the heterozygous deletion of NF1 and NF2, the de novo vemurafenib-resistant patient showed decreased expression of both NF1 and NF2 while vemurafenib-sensitive patients without NF1 or NF2 copy loss did not demonstrate decreased expression of NF1/NF2 by qRT-PCR. To understand the functional role of Nf1 and Nf2 loss and the potential contribution to RAF inhibitor resistance in the hematological system, we performed shRNA-mediated downregulation of Nf1 or Nf2 in Ba/F3 cells stably expressing BRAFV600E. Silencing of either Nf1 or Nf2 alone or concomitant downregulation of Nf1 and Nf2 simultaneously conferred vemurafenib resistance in vitro (Fig. H).
Combined, these data identify several novel drivers of HCL. While activating MAPK mutations are critical for both cHCL and vHCL, our data suggest additional shared cooperating alterations, as well as disease-specific alterations targeting BRAF, KMT2C, and CDKN1B in cHCL and MAP2K1, CCND3, U2AF1, TP53, and KMT2C in vHCL. Finally, these data nominate several novel potential therapeutic approaches for vHCL and identify a novel mechanism of vemurafenib resistance seen clinically.
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Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A ...representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers.
We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation.
From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies.
Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.
Correction to Moore et al. (2020) Moore, Tyler M; Kaczkurkin, Antonia N; Durham, E Leighton ...
Journal of abnormal psychology (1965),
10/2020, Volume:
129, Issue:
7
Journal Article
Reports an error in "Criterion validity and relationships between alternative hierarchical dimensional models of general and specific psychopathology" by Tyler M. Moore, Antonia N. Kaczkurkin, E. ...Leighton Durham, Hee Jung Jeong, Malerie G. McDowell, Randolph M. Dupont, Brooks Applegate, Jennifer L. Tackett, Carlos Cardenas-Iniguez, Omid Kardan, Gaby N. Akcelik, Andrew J. Stier, Monica D. Rosenberg, Donald Hedeker, Marc G. Berman and Benjamin B. Lahey (
, Advanced Online Publication, Jul 16, 2020, np). In the article (http://dx.doi.org/10.1037/abn0000601), an acknowledgment is missing from the author note. The missing acknowledgement is included in the erratum. (The following abstract of the original article appeared in record 2020-50590-001.) Psychopathology can be viewed as a hierarchy of correlated dimensions. Many studies have supported this conceptualization, but they have used alternative statistical models with differing interpretations. In bifactor models, every symptom loads on both the general factor and 1 specific factor (e.g., internalizing), which partitions the total explained variance in each symptom between these orthogonal factors. In second-order models, symptoms load on one of several correlated lower-order factors. These lower-order factors load on a second-order general factor, which is defined by the variance shared by the lower-order factors. Thus, the factors in second-order models are not orthogonal. Choosing between these valid statistical models depends on the hypothesis being tested. Because bifactor models define orthogonal phenotypes with distinct sources of variance, they are optimal for studies of shared and unique associations of the dimensions of psychopathology with external variables putatively relevant to etiology and mechanisms. Concerns have been raised, however, about the reliability of the orthogonal specific factors in bifactor models. We evaluated this concern using parent symptom ratings of 9-10 year olds in the ABCD Study. Psychometric indices indicated that all factors in both bifactor and second-order models exhibited at least adequate construct reliability and estimated replicability. The factors defined in bifactor and second-order models were highly to moderately correlated across models, but have different interpretations. All factors in both models demonstrated significant associations with external criterion variables of theoretical and clinical importance, but the interpretation of such associations in second-order models was ambiguous due to shared variance among factors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Inelastic neutron and x-ray scattering measurements of phonons and spin waves in CuCrO2 were performed over a wide range of temperature, and complemented with first-principles simulations. The phonon ...dispersions and density of states are well reproduced by our density functional cal- culations, and reveal a strong anisotropy of Cu vibrations, with large amplitudes of low-frequency in-plane motions. In addition, we find that spin fluctuations persist above 300 K, far above the N eel temperature for long-range antiferromagnetic order, TN. Modeling of the thermal conductivity, based on our phonon measurements and simulations, reveals a significant anisotropy and indicates that the spin fluctuations above TN constitute a strong source of phonon scattering.
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